Large conductance, calcium-activated potassium channels (BK) are widely distributed and fundamentally important to excitable and secretory cells. These channels comprise a large and diverse class which respond to a combination of voltage and calcium, and possess a large unit conductance (130-300 pS). Through sensitivity to calcium, a major intracellular messenger, calcium-activated potassium channels serve to link basic cellular metabolism to membrane potential. BK channels are present in neurons where they contribute to the repolarizing phase of the action potential, and possibly to transmitter secretion. They are also found in striated and smooth muscle, endocrine and exocrine gland cells, kidney tubules and epithelia. BK channel activity is absolutely dependent upon intracellular calcium, but can be modulated by G-proteins and phosphorylation. These investigators have cloned and expressed a large family of BK-like calcium-activated potassium channels from Drosophila. Although they share an overall architecture with other cloned potassium channels, they differ significantly in primary sequence and many fundamental functional aspects. They propose to use an integrated combination of electrophysiology, molecular biology, and biochemistry to: 1. Determine the mechanisms by which calcium effects channel gating. 2. Determine the molecular basis of the large unit conductance of these channels, and 3. Determine the structure and function of mammalian calcium-activated potassium channels.